GLUTAMATE DEHYDROGENASE AS A NEUROPROTECTIVE TARGET AGAINST BRAIN ISCHEMIA AND REPERFUSION
GLUTAMATE DEHYDROGENASE AS A NEUROPROTECTIVE TARGET AGAINST BRAIN ISCHEMIA AND REPERFUSION
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DOI：
10.1016/j.neuroscience.2016.11.007
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发表时间：
2017-01-06
期刊：
影响因子：
3.3
通讯作者：
Baik, Eun Joo
中科院分区：
文献类型：
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作者：
Kim, A. Young;Jeong, Kyeong-Hoon;Baik, Eun Joo
谷氨酸稳态失调与退行性神经系统疾病有关。谷氨酸脱氢酶（GDH）对于谷氨酸代谢是重要的，并且在扩大三羧酸（TCA）循环中间体α-酮戊二酸（α-KG）的库中起核心作用，其改善整体生物能量学。在高能量需求下，ATP产生的维持导致功能活跃的线粒体。在这里，我们测试是否GDH活性的调制可以挽救缺血/再灌注诱导的神经元死亡在体内模型的中动脉闭塞和体外氧/葡萄糖消耗模型的小鼠。糖酵解抑制剂碘乙酸也用于能量衰竭模型，显著消耗ATP和α-KG。为了刺激GDH活性，使用GDH激活剂2-氨基二环-（2，2，1）-庚烷-2-羧酸和潜在激活剂β-拉帕酮。GDH激活剂恢复了损伤模型中的α-KG和ATP水平，并提供了有效的神经保护作用。我们还发现，β-拉帕酮增加谷氨酸的利用，伴随着细胞外谷氨酸的减少。因此，我们的假设，即线粒体的GDH激活剂增加α-KG生产作为一种替代能源，用于在能量耗尽的条件下的TCA循环得到证实。我们的研究结果表明，增加GDH介导的谷氨酸氧化代表了一种新的治疗干预神经退行性疾病，包括斯托克。(C)2016年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Deregulation of glutamate homeostasis is associated with degenerative neurological disorders. Glutamate dehydrogenase (GDH) is important for glutamate metabolism and plays a central role in expanding the pool of tricarboxylic acid (TCA) cycle intermediate alphaketoglutarate (alpha-KG), which improves overall bioenergetics. Under high energy demand, maintenance of ATP production results in functionally active mitochondria. Here, we tested whether the modulation of GDH activity can rescue ischemia/reperfusion-induced neuronal death in an in vivo mouse model of middle artery occlusion and an in vitro oxygen/glucose depletion model. lodoacetate, an inhibitor of glycolysis, was also used in a model of energy failure, remarkably depleting ATP and a-KG. To stimulate GDH activity, the GDH activator 2-aminobicyclo-(2,2,1)-heptane-2 -carboxylic acid and potential activator beta-lapachone were used. The GDH activators restored alpha-KG and ATP levels in the injury models and provided potent neuroprotection. We also found that beta-lapachone increased glutamate utilization, accompanied by a reduction in extracellular glutamate. Thus, our hypothesis that mitochondria' GDH activators increase alpha-KG production as an alternative energy source for use in the TCA cycle under energy-depleted conditions was confirmed. Our results suggest that increasing GDH-mediated glutamate oxidation represents a new therapeutic intervention for neurodegenerative disorders, including stoke. (C) 2016 IBRO. Published by Elsevier Ltd. All rights reserved.